tbuckley/cabot-search huggingface dataset:
CTIM-20. PROSPECTIVE RANDOMIZED PHASE II PLACEBO-CONTROLLED TRIAL OF SURVAXM PLUS ADJUVANT TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA (SURVIVE)
Authors: Manmeet Ahluwalia, Michael J Ciesielski, Ajay Abad, David A Reardon, Robert Aiken, Marissa Barbaro, Kaylyn Sinicrope, David Peereboom, Yazmin Odia, Andrew Brenner, Vyshak Venur, Ahmed Belal, Jingxin Qiu, Atulya Khosla, Cathy Schilero, Danielle Casucci, Laszlo Mechtler, Robert Fenstermaker
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Newly diagnosed glioblastoma (nGBM) has a dismal prognosis with survival of 15-18 months. Tumor associated “survivin” protein is expressed in &amp;gt;95% of nGBM and is targetable with the use of SurVaxM, shown to be effective at generating cytotoxic T lymphocytes. METHODS nGBM patients are being enrolled in this randomized placebo-controlled trial phase II study. Eligibility Criteria includes age ≥ 18, KPS ≥ 70, IHC confirmed survivin-expression, and residual contrast enhancement of ≤1 cm3 by MRI, within 72 hours of surgical resection. Patients are randomized 3:2 into two arms A:B to treatment with SurVaxM in emulsion with Montanide plus sargramostim (local injection) and standard-of-care TMZ (Arm A), or placebo (saline in emulsion with Montanide) plus saline (local injection) and standard-of-care TMZ (Arm B). There are three active treatment phases in the study with vaccine priming (VP) phase; adjuvant TMZ phase; and Vaccine Maintenance (VM) phase. A total of four (4) priming doses of SurVaxM in Montanide plus sargramostim (“SurVaxM/sargramostim”) or placebo in Montanide/saline (“Placebo/Placebo”) will be administered every two weeks ( ± 3 days) during the priming phase, with subsequent dosing every 8 weeks ( ± 1 week) during the vaccine maintenance phase. After priming doses, SurVaxM/sargramostim or Placebo/Placebo will be administered every 8 weeks ( ± 1 week) until tumor progression or for a maximum of 24 months. The total sample size is of 265 patients, with 159 patients in the SurVaxM arm and 106 patients in the control arm. The primary objective is to determine the overall survival (OS), and the secondary objectives include progression-free survival (PFS), OS at pre-specified time points (OS-15, OS-18 and OS-24), PFS at pre-specified time points (PFS-3, PFS-6 and PFS-12) and evaluation of toxicities. Study duration is expected at 36 months, with enrollment ongoing at several centers and planned for total of 20 participating centers.
RADT-12. PRE- AND POST-OPERATIVE RADIATION TREATMENT PLANNING FOR PATIENTS RECEIVING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: A VOLUMETRIC ANALYSIS
Authors: Cindy Ho, Haley Perlow, Alex Ritter, Yevgeniya Gokun, Jennifer Matsui, Joshua Wang, Mark Damante, Dukagjin Blakaj, Sasha Beyer, Evan Thomas, Russell Lonser, Douglas Hardesty, Raju Raval, Joshua Palmer, James Elder
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Pre-operative stereotactic radiosurgery (SRS) has emerged as a recent treatment option to treat large or symptomatic brain metastases. Compared to post-operative SRS, pre-operative treatment may reduce rates of radiation necrosis (RN) and meningeal disease through treating a smaller treatment volume and by preventing post-operative tumor seeding. We hypothesize that pre-operative radiation volumes will be smaller than post-operative volumes, which in turn may lead to a decreased treatment morbidity. METHODS A retrospective analysis was conducted and patients who had surgical resection and post-operative SRS or fractionated stereotactic radiosurgery (FSRT) for a posterior fossa brain metastasis were eligible for inclusion. Both pre-operative and post-operative MRIs were required to allow for accurate radiation target delineation. A pre-operative tumor volume was added for each patient, and the post-operative clinical treatment volume (CTV) used for radiation treatment was included. Pre-operative tumor and post-operative cavity volumes were compared using Wilcoxon signed rank test. RESULTS 28 patients who received post-operative SRS or FSRT from 1/1/2016-12/31/2020 were included in this analysis. The mean pre-operative tumor volume was 14.9 ccs, and the mean post-operative CTV was 21.0 ccs (p &amp;lt; 0.01). 75% of patients had a smaller initial tumor size compared to the post-operative CTV used for radiation treatment planning. For patients with at least 4 follow up MRIs (n = 8), the size of the post-operative cavity progressively decreased with a mean initial cavity volume of 18.9 ccs and mean follow up volumes of 8.1, 7.1, 6.9, and 6.2 ccs. CONCLUSIONS In this study evaluating patients who received post-operative SRS, the pre-operative tumor volume was lower than the post-operative CTV for most patients. Previous studies including PROPS-BM have shown how pre-operative treatment may reduce the risk of RN because smaller radiation volumes are used. Pre-operative radiosurgery for patients with brain metastases requires prospective validation.
NCOG-34. METASTATIC PAPILLARY TUMOR OF THE PINEAL REGION: ROLE OF STEREOTACTIC IRRADIATION AND ADJUVANT TEMOZOLOMIDE
Authors: Amily Koshy, Esther Kim, Shannon Higgins, Aya Haggiagi
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Papillary tumor of the pineal region (PTPR) is a very rare tumor comprising &amp;lt; 1% of all intracranial neoplasms. It was first included as a distinct tumor entity in the 2007 World Health Organization classification. Due to its rarity, only anecdotal data is currently available to guide management. However, with these tumors being recognized more frequently, further molecular observations and therapeutic experiences are necessary. Herein, we report an unusual case of PTPR with a previously treated leptomeningeal metastasis (LM) whom we successfully managed with Gamma Knife Radiosurgery (GKRS) and adjuvant temozolomide at time of distant brain parenchymal tumor progression. CASE REPORT: A 41-year-old man presented with headache and diplopia in 2015, MRI brain revealed a large cystic enhancing lesion in the pineal region protruding into the third ventricle and causing obstructive hydrocephalus. He had a ventriculoperitoneal shunt placed and underwent partial tumor resection. He then transferred care to our institution and a gross total resection was achieved. Pathology confirmed PTPR. A repeat MRI 15 months later showed evidence of radiographic LM in the cerebellum and he underwent craniospinal proton radiation therapy. He remained stable until January 2020 when a new left temporal heterogeneously enhancing multicystic lesion was identified on surveillance MRI. He underwent subtotal resection of this intra-axial lesion. Histological features of the tumor were similar to his initial tumor. Somatic tumor mutation testing using FoundationOne®CDx did not reveal targetable molecular alterations. Following surgery, he received GKRS and six cycles of adjuvant temozolomide. At 21-month follow up, patient continues to do well. CONCLUSION To our knowledge, this is the first case to describe a metastatic brain intraparenchymal PTPR. We also describe a first case of successful therapeutic strategy for a distant recurrence of PTPR.
CSIG-40. STEAROYL-COA DESATURASE 1 (SCD1) IS REQUIRED FOR WNT SIGNALING TO INDUCE AN APOPTOSIS IN IDH MUTANT GLIOMA
Authors: Lumin Zhang, Tomohiro Yamasaki, Tyrone Dowdy, Adrian Lita, Mark Gilbert, Mioara Larion
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND AND HYPOTHESES SCD1, a major enzyme of saturated fatty acids, has been implicated to be important for tumor metabolic reprograming. Our previous study show that a high level of SCD1 mRNA is associated with IDH1mut lower grade gliomas. IDH1mut glioma cells are more sensitive to SFA induced apoptosis. However, the underlying mechanism remains unclear. In this study, we investigate the functions of SCD1 in IDHmut glioma and the potential contribution of SCD1 for cancer therapy of glioma. STUDY DESIGN AND METHODS The genetically engineered IDH wild-type, IDHmut and patient derived glioma cell lines were used to evaluate SCD1 functions. The expression of proteins were checked by Western-blotting assay. SCD1 was silenced by CRISPR or siRNA. The transcriptome change after SCD1 knockdown was profiled by RNA-seq or single cell RNA-seq (scRNA-seq). RESULTS AND CONCLUSIONS SCD1 transient silencing slowed down the cell growth, suggesting that SCD1 may possess an oncogenic property. RNA-seq analysis revealed that SCD1 inhibition decreased the expression of wnt-signaling pathway genes in IDH-1mut cells. scRNA confirmed that CRISPR SCD1 significantly decreased wnt signaling in the patient cell line Ts603. Therefore, we activated wnt pathway using a small chemical compound, BML-2838. Consistent with recent studies, wnt pathway induction led to a dramatically suppression of glioma cells growth. However, SCD1 silencing reversed this inhibitory effect. Further investigation revealed that SCD1 inhibition reduced the nucleus translocation of phosphorylated beta-catenin. Overall, the results suggest that SCD1 is vital for the onset of wnt pathway in glioma cells. High level of SCD1 expression may render the IDHmut glioma cells more sensitive to wnt pathway induced apoptosis. RELEVANCE AND IMPORTANCE In clinical, the 5-years survival rate of glioma remains low. SCD1 have been considered as a target for glioma therapy, recently. Our data provides a new insight on the strategy to target SCD1 in clinical.
CSIG-28. THE HEDGEHOG GENE EXPRESSION PROGRAM REGULATES LIPID FEEDBACK MECHANISMS UNDERLYING HEDGEHOG-ASSOCIATED MEDULLOBLASTOMA
Authors: Vikas Daggubati, Abrar Choudhury, Akshara Vykunta, Olivier Saulnier, Zachary Gardell, Jeremy Reiter, Michael Taylor, David Raleigh
Journal: Neuro-Oncology (2022)

Abstract Misactivation of the Hedgehog pathway can cause cancers such as medulloblastomas, the most common malignant brain tumors in children. Hedgehog signals are transmitted through primary cilia, where Hedgehog ligands bind to Patched1 and activate Smoothened through interactions with cilia-associated sterol lipids. The gene expression programs driving cellular responses to ciliary Hedgehog signals are incompletely understood. Thus, to define Hedgehog target genes and elucidate mechanisms underlying Hedgehog-associated medulloblastomas, we performed RNA sequencing of cells after treatment with Hedgehog ligands (Shh, Dhh, Ihh), cilia-associated lipids (7b,27-dihydroxycholesterol, 24(S),25-epoxycholesterol), or synthetic lipids or small molecules that activate Smoothened (20(S)-hydroxycholesterol, SAG). Nonspecific gene expression changes were identified by performing RNA sequencing (1) after treatment of CRISPR mediated Smo-/- cells with the same Hedgehog pathway agonists, (2) after treatment with vehicle controls, or (3) after treatment with sterol lipids that are unable to activate Smoothened (7a,27-dihydroxycholesterol). Differentially expressed genes were integrated across RNA sequencing of human medulloblastomas (n=458) or the Math1-Cre SmoM2 mouse genetic model of Hedgehog-associated medulloblastoma. Mechanistic studies validating Hedgehog target genes were performed using CRISPR interference, genetic gain-of-function, molecular biology, quantitative immunofluorescence, or cell biology approaches. RNA sequencing after treatment with Hedgehog pathway agonists identified a core gene expression program comprised of 155 genes driving lipid synthesis, metabolism, signaling, adhesion, or angiogenesis. Integration of transcriptomic datasets revealed a conserved gene expression program driving cellular responses to ciliary Hedgehog signals in human or mouse medulloblastomas, including known target genes such as Gli1 or Ptch1, and novel target genes such as Hsd11b1 or Retnla. Retnla is a regulator of sterol synthase expression, and Hsd11b1 is a sterol synthase that opposes the action of Hsd11b2, a driver and druggable dependency underlying Hedgehog-associated medulloblastoma. In support of these findings, mechanistic studies demonstrated Retnla drives expression of Hsd11b2, and showed Hsd11b1 negatively regulates the Hedgehog pathway.
TMET-22. ENHANCED LIPID METABOLISM IN BRAIN TUMORS: AN EXPLOITABLE METABOLIC VULNERABILITY THROUGH DIET-INDUCED KETOSIS
Authors: Shiva Kant, Pravin Kesarwani, Yi Zhao, Prakash Chinnaiyan
Journal: Neuro-Oncology (2022)

Abstract Enhanced lipid metabolism contributes towards carcinogenesis at multiple levels, serving as a "gain of function" in several cancers, including glioblastoma. Seemingly paradoxical to these findings, pre-clinical investigations have demonstrated anti-tumor activity in mice fed a high fat/low carbohydrate ketogenic diet (KD), both alone and in combination with conventional therapy. Therefore, we sought to define mechanistic underpinnings contributing towards this apparent disconnect. Consistent with previous reports, mice fed a KD demonstrated independent anti-tumor activity and potent synergy with RT when tested in an aggressive glioblastoma orthotopic model. To provide a window into metabolic consequences of a KD in glioblastoma, we performed global metabolomic profiling on tumors and serum from mice fed a standard diet and KD. Although ketosis was confirmed, no change in glucose was observed in serum of KD mice, suggesting presence/absence of carbohydrates might not be contributing to the observed anti-tumor activity. Interestingly, profound intra-tumoral metabolic changes were observed in intracranial tumors from mice fed a KD, with an accumulation of unsaturated fatty acids emerging as a central metabolic node. Intriguingly, recapitulating these findings in culture conditions in vitro, polyunsaturated fatty acid linoleic acid demonstrated anti-proliferative activity, decreased clonogenic capacity, and synergy with RT in GBM cells, recapitulating in vivo findings. This was not observed when cultured with the monounsaturated fatty acid oleic acid. Through a series of investigations, we went on to identify lipid storage homeostasis and lipotoxicity associated with free fatty acid accumulation played a contributory role in the differential activity of these different classes of fatty acids. Importantly, PUFA-rich modified diet showed potent antitumor activity in combination with RT in our preliminary investigation. These studies collectively reaffirm and provide mechanistic underpinnings of the anti-tumor activity of a KD, suggesting that enhanced lipid metabolism in brain tumors may serve as an exploitable metabolic vulnerability through diet modification.
CTIM-28. MULTILAMELLAR MRNA LIPID PARTICLES INDUCE IMMUNOLOGIC REPROGRAMMING IN CANINE AND HUMAN GLIOBLASTOMA PATIENTS
Authors: Hector Mendez-Gomez, Anna DeVries, Brian Stover, Dingpeng Zhang, Adam Grippin, Christina Von Roemeling, Frances Weidert, Aida Karachi, Sadeem Qdaisat, Nagheme Thomas, James McGuiness, Paul Castillo, Jianping Huang, John Ligon, Natalie Silver, Patrick Kellish, Andria Doty, Sheila Carrera-Justiz, Michael Prados, Sabine Mueller, Maryam Rahman, Ashley Ghiaseddin, Duane Mitchell, Elias Sayour
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Although mRNA vaccines have been deployed with great success against COVID-19, unlocking this technology against glioblastoma will necessitate new lipid-nanoparticle formulations that overcome cancer tolerance and immunosuppression. OBJECTIVE/METHODS We sought to develop a novel mRNA vaccine system to make tolerogenic tumor antigens appear more dangerous through use of unmodified nucleosides (pathogen associated molecular patterns, PAMPs) and highly cationic lipid shells that elicit a systemic damage response against cancer antigens. RESULTS We developed a novel vaccine formulation that increases payload packaging of tumor amplified mRNA into multilamellar (onion-shaped) particles for systemic (intravenous) administration. We demonstrate significant immunogenicity and efficacy of multilamellar RNA-NPs in syngeneic murine models for high-grade glioma (KR158b-pp65), and diffuse midline glioma (H3K27M DMG). Remarkably, RNA-NPs significantly improve median survival outcomes of DMG bearing mice beginning therapy at endpoint (Day 35 after midline intracranial implantation). Unlike prototypical mRNA vaccines that activate endosomal toll-like receptors (i.e. TLR7), multilamellar RNA-NPs elicit immunologic response predominantly through intracellular pathogen recognition receptors (RIG-I); long-term survival benefits from RNA-NPs were completely abrogated in RIG-I knockout mice. In canines (pet dogs) with spontaneous gliomas, RNA-NPs elicit massive recruitment/activation of peripheral blood mononuclear cells (PBMCs) which correlate with their trafficking into lymphoreticular organs (in follow-up murine studies). In canines receiving neoadjuvant RNA-NPs, prior to glioma biopsy, we see significant reprogramming of the glioma microenvironment with increased gene signatures for antigen processing/presentation, interferon signaling and cytotoxicity. Upon translation into human clinical trials for glioblastoma patients (NCT04573140), RNA-NPs elicit rapid (within hours) release of cytokines (e.g. IL-1, IL-6, IL-12 TNF-α, interferons) and chemokines (e.g. MIP1α, MCP-1, IP-10), which correlate with mobilization of PBMCs and activation of dendritic cells/CD8 lymphocytes. CONCLUSION First-in-human application of systemic multilamellar RNA-NP vaccines results in significant biologic effects and rapid immunologic reprogramming.
NIMG-54. LOW FRACTIONAL TUMOR BURDEN VOLUME OBTAINED FROM PERFUSION MRI REVEALS SIGNIFICANT SURVIVAL BENEFIT IN MGMT UNMETHYLATED GLIOBLASTOMA
Authors: Melissa Prah, Jennifer Connelly, Kathleen Schmainda
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Standard imaging remains inadequate for the determination of GBM response within the first 3 months following upfront chemoradiation therapy (CRT). Since advanced diffusion and DSC perfusion (pMRI) MRI are currently not included in RANO criteria, greater reliance is placed on MGMT methylation status, with methylated tumors demonstrating survival benefit. While pMRI has demonstrated usefulness following CRT, a newer pMRI biomarker termed Fractional Tumor Burden (FTB) provides both spatial and quantifiable information. The purpose of this study was to evaluate whether advanced MRI including FTB informs a survival benefit beyond MGMT promoter methylation status in newly diagnosed GBM (nGBM). METHODS Consented subjects with nGBM, and known MGMT status who completed standard upfront therapy and had MRI within 6 weeks of CRT completion, were included. Known IDH-mutant tumors were excluded. DSC was collected with the consensus protocol and leakage-corrected relative cerebral blood volume (rCBV) generated. Apparent diffusion coefficient (ADC) was calculated from diffusion MRI (b-value: 0,1000 s/mm2). FTB-defined tumor volumes were calculated from rCBV and delta T1w enhancement. Kaplan-Meier 24-month overall survival (OS) was evaluated for MGMT status and stratified by cohort mean for rCBV (1.3 a.u.) and ADC (1300 x10-6mm2/s), and empirically for FTB (5 ml) (significance: P &amp;gt;.05). RESULTS A total of 43 subjects were included (male/female=21/22; age=57(23-74)). MRI was acquired an average of 29 (12-42) days following CRT. Significant OS differences were confirmed for MGMT methylation (OS=19.08 vs. 10.18 mo; P=.0129). No significant survival differences were found (P &amp;gt;.05) when stratified by rCBV or ADC. While FTB did not provide further OS distinctions in methylated GBM, those with unmethylated MGMT had significant OS benefit when FTB volume was &amp;lt; 5 ml (OS=16.15 vs 8.39 mo; P=.0054). CONCLUSION FTB further informs OS in MGMT promoter unmethylated GBM, where those with lower volume had survival approaching that of methylated subjects.
EXTH-82. THERAPEUTIC TARGETING OF EZH2 AND BET BRD4 IN PEDIATRIC RHABDOID TUMORS
Authors: Yukitomo Ishi, Yongzhan Zhang, Ali Zhang, Takahiro Sasaki, Andrea Piunti, Amreena Suri, Jun Watanabe, Kouki Abe, Manabu Natsumeda, Lihua Zou, Ali Shilatifard, Rintaro Hashizume
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Aberrant activity of the H3K27 modifiers EZH2 and BRD4 is an important oncogenic driver for atypical teratoid/rhabdoid tumor (AT/RT), and each is potentially a possible therapeutic target for treating AT/RT. Thus, targeting distinct histone modifier activities would be an effective approach for treating AT/RT. METHODS The effects of EZH2 and BRD4 inhibition on histone modification, cell proliferation, and cell invasion were analyzed by immunoblotting, MTS assay, colony formation assay, and cell invasion assay. RNA- and chromatin immunoprecipitation-sequencing were used to determine transcriptional and epigenetic changes in AT/RT cells treated with EZH2 and BRD4 inhibitors. We treated mice bearing human AT/RT xenografts with EZH2 and BRD4 inhibitors. Intracranial tumor growth was monitored by bioluminescence imaging, and the therapeutic response was evaluated by animal survival. RESULTS AT/RT cells showed elevated levels of H3K27 trimethylation (H3K27me3) and H3K27 acetylation (H3K27ac), with expression of EZH2 and BRD4, and lack of SMARCB1 proteins. Targeted inhibition of EZH2 and BRD4 activities reduced cell proliferation and invasiveness of AT/RT in association with decreasing H3K27me3 and H3K27ac. Differential genomic occupancy of H3K27me3 and H3K27ac regulated specific gene expression in response to EZH2 and BRD4 inhibitions. Genes associated with DNA-repair pathway was downregulated upon EZH2 and BRD4 inhibition, and the sensitivity to cisplatin was elevated upon combination of EZH2 and BRD4 inhibitors in vitro. A combination of EZH2 and BRD4 inhibition increased the therapeutic benefit in vitro and in vivo, outperforming either monotherapy. CONCLUSION Histone H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is therefore a potential combination therapy for AT/RT.
CSIG-06. RETROSPECTIVE REVIEW OF GLIOMA PATIENTS WITH CONFIRMED MET AMPLIFICATION OR FUSION
Authors: Ramya Tadipatri, Chukwuyem Ekhator, Adela Miller, Jai Grewal, Manmeet Ahluwalia, Ekokobe Fonkem
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The MET pathway is a key oncogenic pathway in gliomas and is involved in tumor survival, angiogenesis, and invasion. MET alterations have been increasingly identified as a potential therapeutic target. METHODS Our objective was to further characterize the natural history of gliomas which harbor MET alterations and study outcomes as determined by progression free survival (PFS) and overall survival (OS). RESULTS We identified 22 glioma patients seen at our institution between 2015 and 2021 who had a MET alteration confirmed through comprehensive molecular profiling. There were 18 grade 4 astrocytomas/glioblastomas, 3 grade 3 gliomas (2 astrocytomas, 1 oligodendroglioma), and 1 grade 2 glioma (oligodendroglioma). MET amplification was observed in 13 patients and fusion in 16 patients , with 7 patients carrying both amplification and fusion alterations. MET fusion partners included PTPRZ1 (8 patients), CAPZA2 (6 patients), and ST7 (3 patients). Median OS was 12.8 months, and median PFS was 8.47 months. IDH1/2 mutation was associated with significantly improved survival, with an estimated OS of 146 months for IDH1/2 mutant tumors and 17.9 months for IDH1/2 wildtype tumors (p&amp;lt; 0.001), MGMT methylation status had no significant survival impact. No significant survival differences were observed between the fusion only, amplification only, and combined fusion and amplification groups. No therapy was predictive of improved outcomes. CONCLUSION MET amplification and fusion alterations were observed in both low and high grade gliomas, suggesting that they may be involved in early tumorigenesis. Survival outcomes were poor compared with historical data, with no differences observed between treatment groups, suggesting that current therapeutic modalities may be inadequate. This study indicates that MET may be an appropriate therapeutic target, laying the groundwork for clinical trials investigating MET-targeted agents.